Mucinous Syringometaplasia: Surrounding Acanthosis With Hyperkeratosis Tends to Conceal the Change.

A 57-year-old man had a 2-year history of a painful nodule on the right sole. Physical examination revealed an 8 × 8 mm hyperkeratotic plaque with a central fissure. Excisional biopsy disclosed epithelial invagination surrounded by the acanthotic epidermis with parakeratotic hyperkeratosis and focal hypergranulosis. The invaginated epithelium lacked a cornified layer and was composed of a mixture of small basaloid squamous cells and goblet cells showing tubular structures. The patient was diagnosed with mucinous syringometaplasia. Our literature review established that surrounding acanthosis with hyperkeratosis typically tends to conceal mucinous syringometaplastic changes. Because mucinous syringometaplasia often presents as an asymptomatic papule/nodule with no distinct ulcer, fissure, or depressed area, cases may be overlooked.

Cutaneous Histiocytic Sarcoma With Cellular Cannibalism.

Cutaneous histiocytic sarcoma (HS) is a rare malignant tumor. An 82-year-old woman presented with a 4 × 2-cm irregular-shaped red nodule on the left posterior scalp. A biopsy specimen revealed sheets of pleomorphic atypical cells in the dermis and subcutis. A diagnosis of HS was made based on the results of a panel of immunohistochemical stains that revealed positivity of leukocyte common antigen, CD4, CD163, and HLA-DR. At the time of resection, the tumor grew rapidly to 12 × 6.5 × 5 cm in size in 2 months. The resected tumor comprised round, oval, plasmacytoid, and spindled cells. Signet-ring cell type tumor cells were also observed. The histiocytic nature of HS was confirmed owing to the presence of cellular cannibalism, emperipolesis, Langhans giant cell-like cells, Touton giant cell-like cells, foreign-body giant cell-like cells, and hemosiderin laden cells. In some foci, a storiform pattern and fascicular pattern were occasionally observed. Local recurrence occurred shortly after resection. Subsequent radiation therapy showed insufficient effectiveness. It is challenging to make a diagnosis of HS without performing immunohistochemical studies; however, a variety of histiocytic features confirmed in hematoxylin and eosin-stained sections may suggest HS.

Sarcomatoid Variant of Primary Cutaneous Anaplastic Large Cell Lymphoma.

Sarcomatoid variant of primary cutaneous anaplastic large cell lymphoma is rare and is a diagnostic challenge. Clinical manifestation often mimics that of an infectious disease. Predominance of spindle cells in the biopsy specimen prevents from suspecting lymphoma. Here, we report the fourth case of this entity with good prognosis. A 30-year-old woman presented with several nodules on the whole body. The biopsy revealed infiltration of spindle cells in the dermis with myxomatous background. The spindle cells were positive for CD4 and CD30 and negative for CD3, CD8, CD20, and anaplastic lymphoma kinase. Although most of the skin lesions spontaneously resolved, a new red nodule progressively expanded on the left axilla. Finally, the patient received chemotherapy, which resulted in complete remission. The patient is free of disease for 18 months.

Adenodermatofibroma possessing dilated glandular structures with eccrine features: A case study.

Adenodermatofibroma is a newly recognized variant of dermatofibroma characterized by dense proliferation of fibroblasts and histiocytes admixed with dilated glandular structures showing apocrine secretion. Only five cases of adenodermatofibroma have been reported to date. We report an additional case of adenodermatofibroma on the back of a 67-year-old female. In addition to the dilated glandular structures, nondilated eccrine units were present at the upper periphery of the lesion, above which the normal eccrine glands reside. Although decapitation secretion was observed in the nondilated eccrine units at the upper periphery of the lesion, this was not observed in the dilated glandular structures. The inner cells of the dilated glandular structures were S-100 positive, similar to those of the secretory portion of eccrine glands. We considered the glandular structures in our patient were derived from the entrapped eccrine units. We suggest that the term "apocrine metaplasia" be applied to eccrine units showing decapitation secretion.

Angiotropic syringomatous carcinoma.

Syringomatous carcinoma (SC) is a slow-growing malignant skin tumor that usually affects the face or scalp. An 83-year-old female developed SC on the sole, a rare location. Histopathologically, numerous ducts with few keratinizing cysts were seen in the upper dermis, and cords, strands and nests with sclerotic stroma were seen in the deep dermis and subcutis. In addition to the perineural and intraneural invasion of the tumor, the tumor cells had also invaded the vessel walls. There was no intravasation of tumor cells or interruption of the endothelium. Because melanoma with vascular wall invasion without intravasation of melanoma cells or interruption of the endothelium has been called angiotropic melanoma, we termed the present tumor angiotropic SC. Tumor cells showed wide local invasion.

Anti-early endosome antigen 1 autoantibodies were detected in a pemphigus-like patient but not in the majority of pemphigus diseases.

Although the major autoantigens in classic pemphigus are desmogleins, sera from various types of pemphigus react with a number of other molecules, including desmocollins and plakin proteins. However, other novel pemphigus-related autoantigens remain to be identified. In this study, immunoblotting for serum from an atypical autoimmune bullous disease patient identified an unknown 175 kDa protein. Subsequent studies using two-dimensional gel electrophoresis, immunoblotting and mass-spectrometry identified the 175 kDa protein as early endosome antigen 1 (EEA1). This finding was confirmed by subsequent immunological studies, including indirect immunofluorescence of skin and cultured keratinocytes, two-dimensional gel electrophoresis and immunoblotting with anti-EEA1 polyclonal antibody, and preabsorption with EEA1 recombinant protein. Finally, we developed a novel BIOCHIP assay using full-length EEA1 recombinant protein to detect anti-EEA1 antibodies. However, none of 35 sera from various types of pemphigus showed anti-EEA1 antibodies in the BIOCHIP assay, with the exception of the serum from the index case. In addition, various findings in the index case did not suggest pathogenic role of anti-EEA1 autoantibodies. Therefore, although we successfully identified the 175 kDa protein reacted by a serum of an atypical pemphigus-like patient as EEA1, novel BIOCHIP study for other pemphigus sera indicated that EEA1 is not a common and pathogenic autoantigen in pemphigus.

Comparative Study of Direct Immunofluorescence in Discoid Lupus Erythematosus and Bullous Pemphigoid.

Immunoreactants are found in the epidermal basement membrane in both lupus erythematosus and bullous pemphigoid (BP). To our knowledge, there are no comparative studies on direct immunofluorescence (DIF) of discoid lupus erythematosus (DLE) and BP. The authors studied DIF of lesional skins in 9 patients (2 males and 7 females) with DLE and 29 patients (11 males and 18 females) with BP to disclose the difference between these 2 diseases. IgG deposition was significantly more frequent at the epidermal basement membrane zone (BMZ) in the BP group than in the DLE group; however, IgA and IgM depositions were significantly more frequent at both the epidermal and follicular BMZs in the DLE group than in the BP group. In addition, the mean number of positive immunoreactants at both the epidermal and follicular BMZs was significantly larger in the DLE group than in the BP group. On an average, ≥3 immunoreactants were seen at the epidermal and follicular BMZs in DLE, whereas ≤2.5 immunoreactants were seen in BP. DIF may contribute to the differentiation between these 2 diseases.

Epidermal polymeric immunoglobulin receptors: leads from intraepidermal neutrophilic IgA dermatosis-type IgA pemphigus.

In this study, we attempted to identify unknown autoantigen for intraepidermal neutrophilic IgA dermatosis-type IgA pemphigus by novel IgA-specific immunoprecipitation. Mass-spectrometry study identified polymeric immunoglobulin receptor (PIGR) as the candidate protein, and we confirmed that PIGR expressed in both epidermis and cultured keratinocytes. Eukaryotic recombinant protein of PIGR expressed in COS7 cells was reacted with both patient and normal sera, indicating that PIGR binds physiologically to IgA. To detect antigen-specific binding by IgA autoantibodies, we performed several experiments using deglycosylated PIGR and F(ab)2 fragments from patient sera. However, these analyses suggested that patient IgA bound physiologically, but not immunologically, to PIGR. Nevertheless, our study provided two important insights. Newly developed IgA-immunoprecipitation system should be a useful tool in the future study of identification of antigens for IgA autoantibodies. Detection of epidermal PIGR in this study confirmed previous results and indicated possible immunological role of PIGR in epidermis.

Coexistence of autoimmune bullous diseases (AIBDs) and psoriasis: A series of 145 cases.

BACKGROUND: Many case reports have described the coexistence of autoimmune bullous diseases (AIBDs) and psoriasis. Among them, anti-laminin γ1 (p200) pemphigoid is the best known. OBJECTIVES: We sought to characterize patients with AIBDs and psoriasis and to investigate common AIBDs occurring in these patients. METHODS: This retrospective study included 145 patients with coexisting AIBD and psoriasis given a diagnosis from January 1, 1996, to July 31, 2013, at an academic dermatology department. Of these, 134 were consultation cases regarding AIBD diagnosis. RESULTS: Ratio of male to female patients was 5.7:1. Psoriasis onset preceded AIBD onset in most patients. Mean age at AIBD onset was 65.4 years, and mean duration between psoriasis and AIBD onset was 14.6 years. Most cases had single AIBD, whereas 16 cases had combined AIBDs. Bullous pemphigoid was the most prevalent (63.4%) followed by anti-laminin γ1 pemphigoid (37.2%). LIMITATIONS: Consultation cases may not have included mild AIBD cases. CONCLUSION: This study confirmed the association of psoriasis and anti-laminin γ1 pemphigoid. However, because bullous pemphigoid is a much more common disease, it is seen more frequently in patients with psoriasis than anti-laminin γ1 pemphigoid.

Signalling pathways in pemphigus vulgaris.

Acantholysis in pemphigus vulgaris is induced by binding of autoantibodies to desmoglein 3 (Dsg3). The roles of signalling pathways on development of acantholysis have recently been extensively studied. In the study by Sayar et al., recently published in Exp Dermatol, epidermal growth factor receptor (EGFR) signalling was activated in both in vivo and in vitro pemphigus vulgaris experimental models. However, while EGFR inhibitors suppressed activity of p38 mitogen-activated protein kinase (p38MAPK) linearly, they suppressed activity of c-Myc and acantholysis in a non-linear, V-shaped relationship. These findings indicated complicated interactions among EGFR, p38MAPK and c-Myc in pemphigus vulgaris pathology.

Distinct protein expression and activity of transglutaminases found in different epidermal tumors.

We investigated protein expression and in situ activity of transglutaminases (TGs) in normal skin and various epidermal neoplasms. In normal skin, TG1 protein expression and TG activity were found at keratinocyte cell membranes in upper epidermis and granular layer, respectively. In seborrhoeic keratosis, TG1 protein was expressed evenly throughout tumors, while TG activity increased in gradient fashion from lower tumor area to cornified layer. In squamous cell carcinoma, TG1 protein was expressed at inner side of cell membranes, whereas TG activity was found in cytoplasm predominantly at horn pearls. In basal cell carcinoma, weak TG activity was found in cytoplasm of all tumor cells without the presence of TG1 protein. Immunoblotting and in situ activity assays using specific substrate peptides confirmed that TG2, but not TG1, contributed to the TG activity. These results suggested that different expression and activation of TGs may contribute to characteristics of the skin tumors.

Mutation-dependent effects on mRNA and protein expressions in cultured keratinocytes of Hailey-Hailey disease.

Hailey-Hailey disease (HHD) is a dominantly inherited skin disease caused by mutations in ATP2C1 gene, which encodes secretory pathway Ca(2+) /Mn(2+) -ATPase protein 1. The precise mechanism remains unclear. In this study, to understand molecular basis of HHD, we examined expression of mRNA and protein in cultured keratinocytes derived from three HHD patients with different mutations. We showed that reduced expression of mRNA and protein in patient with p.Gln504X, but not in patients with p.Pro307His and c.1308+1G>A. RT-PCR analysis for patient with c.1308+1G>A revealed in-frame exon skipping. Reduction of mRNA and protein in p.Gln504X was considered to be caused by nonsense-mediated mRNA decay. p.Pro307His located adjacent to Ca(2+) -binding residue may induced conformational change, which leads to defective Ca(2+) transport. In-frame shorter transcript caused by c.1308+1G>A may have slightly reduced activity, which accounted for mild phenotype of the patient. These results clarified the pathogenic effects of different causative mutations in development of skin lesions.

B-cell activating factor detected on both naïve and memory B cells in bullous pemphigoid.

B-cell activating factor (BAFF), an important immune regulatory cytokine, is involved in development of autoimmune diseases. Although BAFF is expressed in various cells, including dendritic cells (DCs) and monocytes, BAFF expression on B cells has not been well documented. In the present study, BAFF molecules on DCs and naïve and memory B cells in autoimmune bullous diseases, including pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid (BP), were analysed by flow cytometry. Compared with healthy controls (HC), BAFF expression on naïve and memory B cells increased significantly in BP. No difference in BAFF receptor expression in naïve and memory B cells was shown among all study groups. Furthermore, BAFF expression in both naïve and memory B cells of BP, but not HC, was detected by confocal microscopic analysis. These results implied that BAFF expressed by B cells may play a pathogenic role in autoimmune bullous diseases, particularly BP.

Human dermal fibroblast migration induced by fibronectin in autocrine and paracrine manners.

Although fibronectin (FN) is known as a chemoattractant for human dermal fibroblasts (HDFs), it is unclear whether HDF migration is stimulated by FN produced by HDFs (autocrine manner) or by keratinocytes (paracrine manner). In this study, we investigated HDF migration by Boyden chamber assay using conditioned media from HDFs and HaCaT cells (keratinocyte cell line). Immunoblotting and enzyme-linked immunosorbent assay revealed that FN existed in both conditioned media. Boyden chamber assay showed both conditioned media stimulated HDF migration, which was inhibited by anti-FN antibody. Antibodies to both integrin ß1and ß3 subunits inhibited HDF migration induced by HDF-conditioned medium almost completely and that by HaCaT cell-conditioned medium with 50-60%. These results suggested that HDF migration was stimulated by FN in both autocrine and paracrine manners. However, the mechanisms of HDF migration by FN, particularly the role of integrin ß1 and ß3 subunits, were slightly different between autocrine and paracrine manners.

Locations of acantholysis in pemphigus vulgaris and pemphigus foliaceus.

BACKGROUND: Acantholysis in pemphigus vulgaris (PV) and pemphigus foliaceus (PF) occurs predominantly in the suprabasal area and the granular layer, respectively. However, acantholysis can occasionally be observed in unusual locations. METHODS: We retrospectively studied the acantholysis locations in 35 PV and 27 PF cases, and analyzed them using the index value of Desmoglein (Dsg) 1 and Dsg3 by enzyme-linked immunosorbent assay, clinical data, and inflammatory cells. We also analyzed the relationship between clinical subtype and various parameters. RESULTS: In PV, acantholysis was noted in the suprabasal area in 3 cases, in the lower half of the epidermis in 19 cases, and throughout the epidermis in 13 cases. In PF, acantholysis was observed in the granular layer in 6 cases, in the upper half of the epidermis in 14 cases, and throughout the epidermis in 7 cases. Mean index value of Dsg1 in PV patients with acantholysis throughout the epidermis was 2-fold higher than other PV patients. Neutrophils tended to infiltrate the dermis and epidermis more in PF than in PV. CONCLUSIONS: Higher Dsg1 index values seem to correlate with acantholysis in the upper part of the epidermis in PV. Neutrophils may play some role in unusual acantholysis locations in PF.

Combination therapy of fexofenadine and montelukast is effective in prurigo nodularis and pemphigoid nodularis.

In this study, we report on the efficacy of combination therapy of second-generation antihistamine antagonist, fexofenadine hydrochloride, and leukotriene receptor inhibitor, montelukast sodium, for the treatment of 15 prurigo nodularis or pemphigoid nodularis patients, in whom conventional therapy was ineffective. All patients received 10 mg montelukast once a day and 240 mg fexofenadine twice a day for 4 weeks in addition to other medications they had been taking. We assessed the manifestations of the lesions and itching intensity before and after the therapy, and we evaluated each patient as (i) markedly improved, (ii) improved, (iii) slightly improved, (iv) no change, (v) worse. Two patients (13.3%) were evaluated as markedly improved, and the lesions of one patient completely disappeared. Three patients (20.0%) were evaluated as improved, and six patients (40.0%) as slightly improved. Thus, 11 of 15 cases (73.3%) improved by combination therapy of fexofenadine and montelukast, in which nine cases (75.0%) of prurigo nodularis and two cases (66.7%) of pemphigoid nodularis were involved. No patients revealed any side effects. This study revealed that combination therapy of fexofenadine and montelukast was effective for some patients with conventional therapy-resistant prurigo nodularis and pemphigoid nodularis.

Potential mesenchymal stem cell therapy for skin diseases.

Mesenchymal stem cells (MSCs) are non-haematopoietic cells that reside in most tissues including adult bone marrow. MSCs have recently been extensively studied and used for clinical therapies, including skin wound healing. However, there are still many questions to be answered. In the viewpoint entitled 'Mesenchymal stem cell therapy in skin: why and what for?', Dr. Khosrotehrani provided a comprehensive overview for MSC properties and current progresses on clinical applications for various skin conditions. This viewpoint is therefore very helpful for both dermatologists and basic skin researchers to understand stem cells researches.